The treatment of cancer diseases is of great importance in medicine. There is a worldwide need for effective cancer therapies in order to achieve a treatment which is appropriate to a patient and is target-orientated. This can be seen in the large number of scientific studies which have recently appeared in the fields of applied oncology and fundamental research relating to cancer therapy.
The effects of tumor inhibitors are due to a very wide variety of mechanisms, only some of which are known. It is not unusual for known tumor drugs to be found to have new mechanisms of action. This is also to be expected in the case of the compounds according to the invention. Many tumor drugs act by way of mechanisms such as blockading the mechanism of cell division in the cell, preventing the tumor from being supplied with nutrients and oxygen (antiangiogenesis), preventing metastasis, preventing the reception and the onward transmission of growth signals to the tumor cell or forcing the tumor cell into programed cell death (apoptosis).
Because they have different mechanisms of action, including interacting with different intracellular targets, the clinically relevant cytostatic agents are frequently administered in combination in order to achieve a synergistic therapeutic effect.
Indole derivatives are used in a great variety of ways as pharmacodynamically active compounds and as building blocks for synthesis in pharmaceutical chemistry. Documents WO 99/51224 A1 and WO 01/22954 A1 describe indol-3-yl derivatives which have an antineoplastic effect and which can be substituted by a large number of groups, including by 2-, 3-, 4- and 8-quinoline radicals or 2-, 3-, 4-, 5- and 6-pyridine radicals. A 2-methyl-8-quinolinyl group is mentioned in Example 60 as being a substituent on the amide group. However, no biological properties are mentioned. WO 99/55696 A1 describes substituted hydroxyindoles as being inhibitors of phosphodiesterase 4. However, the compounds according to the invention are not reported to have any antineoplastic activity, nor is it suggested that they might have this activity.
WO 02/08225 A1 describes 2-(1H-indol-3-yl)-2-oxoacetamide derivatives which have an antineoplastic effect in relation to solid tumors. However, there is no mention of specific implementation examples containing quinoline, pyridopyrazine or indazolyl radicals.
Patent specification WO 00/67802 describes indole-3-glyoxylamides which are substituted by relatively long-chain fatty acids as being potential antineoplastic agents. However, there is no mention of specific implementation examples containing quinoline, pyridopyrazine or indazolyl radicals. Nor are any biological data given with regard to such implementation examples.
The publication by W.-T. Li et al. (J. Med. Chem. 2003, 46, 1706 ff.) describes N-heterocyclic indolylglyoxylamides as being orally active compounds which possess antineoplastic activity. However, no information is provided as regards their mechanism of action.
Patent application WO 03/022280 A2 describes 3-glyoxylamideindoles and their use as drugs for antineoplastic treatment. Their general formula also includes 6-quinoline derivatives. In addition, two examples containing a 6-quinoline radical are mentioned as implementation examples and verified by means of biological results. However, there is no mention of specific implementation examples containing pyridopyrazine or indazolyl radicals.
U.S. application Ser. No. 03/0181482 A1 describes novel indolylglyoxylamides. In this case, the compounds according to the invention are described as being antineoplastic agents possessing cytotoxic activity and as being angiogenesis inhibitors. In addition to this, a 6-quinoline derivative is shown as an implementation example (compound 3; p. 10) and verified by means of antiproliferative data (see p. 19; Tables 1a and 1b) and antiangiogenic properties (see p. 20). However, there is no mention of specific implementation examples containing pyridopyrazine or indazolyl radicals.
The Applicant's WO 02/10152 A2 already describes a second class of indole derivatives for treating tumors. In this document, the active compound N-(2-methyl-6-quinolyl)-[1-(4-chlorobenzyl)indol-3-yl]glyoxylamide, inter alia, was tested for its antiproliferative effect on a variety of tumor cell lines.
Clinically tested compounds which either bind to the microtubules (paclitaxel and vincristine) or inhibit topoisomerase II (doxorubicin, etoposide and mitoxantrone) are at present being successfully employed in cancer therapy against, inter alia, breast cancer, ovarian cancer, stomach cancer and lung cancer, and in Kaposi's sarcoma and in leukemias. However, their use is limited by the appearance of drug resistances and also by serious neurological, gastrointestinal, cardiovascular and hepatic side effects.